D 2-(6-Substituted-2-naphthyl)-propanals

ABSTRACT

The d 2-(6-substituted-2-naphthyl)propanals of this invention are prepared by oxidizing the corresponding 2-(6-substituted-2naphtyl)-1-propanols or by reducing d 2-(6-substituted-2naphthyl)propionic acids, the 6-substituent being a methyl, ethyl, isopropyl, cyclopropyl, trifluoromethyl, vinyl, ethynyl, fluoro, chloro, methoxy, methoxymethyloxy, difluoromethoxy, methylthio, methoxymethylthio or difluoromethylthio group. The products have anti-inflammatory, analgesic and anti-pyretic activities.

United States Patet Fried et a1.

1 51 June 2 1, 1975 1 ID) 2-(6-SUBSTITlUTIED-2-NAPHTIHWL)- [PROPANAILS [75] Inventors: John II. Fried; Ian T. Harrison,

both of Palo Alto, Calif.

[73] Assignee: Syntex Corporation, Panama [22] Filed: Oct. 27, 11972 [21] Appl. No.: 301,595

Related US. Application Data [63] Continuation of Ser. No. 865,216. Oct. 9, 1969, abandoned. which is a continuation-in-part of Ser. No. 741.900, July 2. 1968, Pat. No. 3,626,012, and :1 continuation-in-part of Ser. No. 814,855, April 9, 1969. Pat. No. 3,663,713.

[52] IU.S. CI. 260/599; 260/600; 424/333; 260/515 IR [51] Int. CI. C076 47/48 [58] Field of Search 260/599, 600

[56] References Cited UNITED STATES PATENTS 3,626,012 12/1971 Fried et a1 260/600 OTHER PUBLICATIONS Stork et 211., Jour. Amer. Chem. Soc., Vol. 84 (1962) pages 284292.

Primary E.\'aminerBernard Helfin Attorney, Agent, or FirmJoseph l. Hirsch; William E. Walker [57] ABSTRAQT The d 2-(6-substituted-2-naphthyl)propanals of this invention are prepared by oxidizing the corresponding 2-(6-substituted-2-naphtyl)-l-propanols or by reducing (1 2-(eubstituted-Z-naphthyl)propionic acids, the 6-substituent being a methyl, ethyl, isopropyl, cyclopropyl, trifluoromethyl, vinyl, ethynyl, fluoro, chloro, methoxy, methoxymethyloxy, difluoromethoxy, methylthio, methoxymethylthio or difluoromethylthio group. The products have anti-inflammatory. analgesic and anti-pyretic activities.

6 Claims, No Drawings 2-(6-SUlBSTlTUTED-2-NAPHTHYL)FRQFANALS This is a continuation of application Ser. No. 865,216, filed Oct, 9, 1969 and now abandoned, which is a continuation-impart of US. patent applications Ser. No. 741,900 filed July 2, 1968, now US. Pat. No. 3,626,012, and Ser. No. 814,855 filed Apr. 9, 1969, now US. Pat. No. 3,663,713.

This invention relates to d 2-(6-substituted-2- naphthyl)-propanals.

The d 2-(6-substituted-2-naphthyl)propanals of this invention can be represented by the following general formula:

1n the above formula, R is a methyl, ethyl, isopropyl, cyclopropyl, trifluoromethyl, vinyl, ethynyl, fluoro, chloro, methoxy, methoxymethyloxy, difluoromethoxy, methylthio, methoxymethylthio or difluoromethylthio group.

The compounds of Formula 111 exhibit antiinilammatory, analgesic, and anti-pyretic activities; accordingly, these compounds are employed in the treatment and alleviation of inflammation pain and pyrexia in mammals.

The compounds of Formula 111 are especially useful in the treatment of inflammation, such as inflammatory conditions of the muscular skeletal system, skeletal joints and otherr tissues. Accordingly, these compounds are useful in the treatment of conditions characterized by inflammation, such as rheumatism, contu-' sion, lacerations, arthritis, bone fractures, posttraumatic conditions and gout. in those cases in which the above conditions include pain and pyrexia coupled with inflammation, the instant compounds are useful for the relief of these conditions as well as the inflammation.

A measure of anti-inflammatory activity according to the Carrageenin induced endema in Winter et al. The Proceedings of The Society for Experimental Biology and Medicine, Vol. 1 l l, 544 (1962) shows d 2-(6-methoxy- 2-naphthyl)propanal to have 8 times the activity of phenyl butazone.

The preferred manner of administration is oral administration which provides the use of the convenient daily dosage regimen which can be adjusted accordingly to the degree of affliction. Generally, a daily dose of from 0.1 to 60 mg. of the active compound per kilogram of body weight of the mammal is employed. Most conditions respond to the treatment comprising a dosage level in the order of 0.5 to mg. For such oral administration a pharmaceutically acceptable nontoxic composition can be formed by the incorporation of any of the normally employed excipients. Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glyceryl monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene glycol, water, ethanol and the like. These compositions take the forms of solutions, suspensions, tablets,

- Clll O CH3 LCIl -OH MT/(II) 1n the above formulas, R is as previously defined.

The compounds of Formula Ill can be prepared from the corresponding d 2-(6-substituted-2-naphthyl)propionic acids represented by Formula 1 by the following procedure. The latter compounds are first converted to the corresponding acid chlorides by reaction with thionyl chloride in benzene under reflux followed by evaporation of the solvent. The residual acid chloride is then treated with 2 equivalents of lithium aluminum tritertiarybutoxyhydride in an ether solvent such as tetrahydrofuran, tetrahydropyran, dimethoxyethane and the like at a temperature of from to 0C for from 30 minutes to 12 hours to yield the compounds of Formula 111 which can be recovered by conventional procedures. For example, the reaction mixture can be mixed with water, extracted with benzene. The benzene phase can then be evaporated in vacuo to dryness, and the residue recrystallized from dichloromethane-hexane.

The preferred process for preparing the compounds of Formula 111 comprises oxidizing the optical isomer propanols of Formula 11 corresponding to the respective d 2-(6-substituted-2-naphthyl)propionic acids with chromium trioxide-pyridine complex, the molar ratio of the complex to the compounds of Formula 11 being within the range of from 0.821 to 10:1, preferably about 5:1. The reaction is conducted in an inert organic solvent such as a halogenated hyrocarbon, e.g. dichloromethane, chloroform, carbon tetrachloride, etc.; hydrocarbons such as hexane, heptane, benzene, toluene, and the like; amines such as dimethylaniline, pyridine, collidine, quinoline, lutidine, etc.; and ethers such as tetrahydrofuran, tetrahydropyran, dimethoxyethane, diethylether and the like. The reaction is carried out at a temperature of from 0 to 60 C, the time required being dependent upon the reaction temperature. Times of from 1 to 48 hours are usually sufficient. The compounds of Formula 11 are then isolated from the reaction mixture by conventional procedures. For example, the reaction mixture can be chromatographed on silica gel, eluting with dichloromethane to yield the compounds of Formula 11 which can be crystallized from dichloromethanehexane.

Compounds of Formula 1 can be prepared by any of several methods. One such method by which they can beprepar'ed is described in U.S. applications Ser. No. .,60 8,99 7, filed Jan. 13, 1967 and Ser. No. 694,771, filed Dec. 7 l 96 7;and both now abandoned. This method involves'fthe'f reaction of a. B-substituted naphthalene with acetyl chloride in nitrobenzene in the presence of 5 at least 3 molarequivalents of aluminum chloride to afford the corresponding 6-substituted-2- acetylnaphthalene derivative. The resulting derivative is heated with morpholine in the presence of sulfur at about 150C; the resulting product is refluxed with con- ,centrated hydrochloric acid to furnish the corresponding 2-(6-substituted-2 naphthyl)acetic acid derivative. The addition of a methyl group at the C-2 position is carried out by esterifying the 2-( 6-substituted-2-naphthyl)acetic acid derivative by conventional methods such as by treatment with a diazoalkane, such as diazomethane, in ether or with an alkanol such as methanol,

in the presence of boron trifluoride to afford the corre- '-ti ve biological degradation or'by the preparation of diastereo isomer salts of the 2-(6-substituted-2-naph- ""thyl')pr opioni c' acidlderivatives with resolved optically :a ctive" 'aminebase s-such as cinchonidine and then sepa- "ratiii'g the thus formed disastereo isomers by cleaved *ci'y'stalli z'ationjThe separated diastereo isomer salts are 'then'acid cleaves to yield the respective d 2-(6- sirbstituted-Z-naphthyl)propionic acid derivatives.

' The compounds of Formula II together with methods 35 for their preparation have been described in United prepared by reducing the compounds of Formula I with States application Ser. No. 741,904 filed July 2, 1968, now U.S. Pat. No. 3,641,161. For example, they can be lithium aluminum hydride in an inert organic ether'solvent. The compounds of Formula I are treated with'at least 0.75 molar equivalents of lithium aluminum hydr'ide', preferably from 1 to 2.5 molar equivalents. Suitabl inert organic ethers include diethyl ether, dipropyl ether, diisopropyl ether,dibutyl ether, tetrahydrofuran, tetrahydropyran, dimethoxyethane *and the like. The

""bly between 15 and 45C.

reaction is carried out at atemperature between C and the boiling point of the solvent employed, prefera- The compounds of Formula II are then isolated by ';'destroying the excess lithium aluminum hydride, if any, --such as by adding excess ethyl acetate. The mixture is 2 then diluted with water, filtered and extracted with an inert organic solvent immiscible with water. The or- P ganic phase can be evaporated to dryness, and the compou'n'ds of Formula ll obtained by recrystallization from i g. of acet'yl chloride, and 20 ml. of nitrobenzene, there iniEPXxATioN 1 To'a mixture of 1.6 g. of 2-methoxynaphthalene, 1.6

are added 4.0 g. of aluminum chloride. The resulting mixture is stirred for 48 hours at 25C; then it is washed with wateruntil free of chloride ion. The mixture is extracted with methylene chloride; the extracts are 4 dried over sodium sulfate and evaporated under reduced pressure. The residue, 2-acetyl-6- methoxynaphthalene, is refluxed in 2 ml. of morpholine containing one -half gram of sulfurvfor 2 hours; the reaction mixtureis then filtered andevaporated. The resulting reaction'derivati ve is extracted with diethyl ether; the extracts are combined and evaporated. The residue is refluxed in 10 ml. of concentrated hydrochloric acid for 2 hours, cooled to 25C, and neutralized with aqueous sodium hydroxide. The mixture is then extracted with ether and the extracts are combined, washed with water to neutrality, dried and evaporated to yield 2-(6- methoxy-2-naphthyl)acetic acid.

Similarly, 2-(6-methyl-2-naphthyl)acetic acid, 2-(6-ethyl-2-naphthyl)acetic acid, 2-(6-isopropyl-2-naphthyl)acetic acid, 2-(6-cyclopropyl-2-naphthyl)acetic acid, 2-(6-trifluoromethyl-2-naphthyl)acetic acid, 2-(6-vinyl-2-naphthyl)acetic acid, 2-(6-ethynyl-2-naphthyl)acetic acid, 2-(6-fluoro-2-naphthyl)acetic acid, 2-(6-chloro-2-naphthyl)acetic acid, 2-(6-methoxy-2-naphthyl)acetic acid, 2-( 6-methoxymethyloxy-2-naphthyl )acetic acid, 2-(6-difluoromethoxy-Z-naphthyl)acetic acid, 2-(6-methylthio-2-naphthyl)acetic acid, 2-(6-methoxymethylthio-2-naphthyl)acetic acid, and 2-(6-difluoromethylthio-2-naphthyl)acetic acid are prepared from the corresponding B-substituted naphthalene by this procedure.

PREPARATION 2 To a mixture of 22 g. of methyl 2-(6-methoxy-2- naphthyl)-acetate (prepared by treating 20.5 g. of 2-( 6- methoxy-2-naphthyl)acetic acid with 4.5g. of diazomethane in ether), and 2.5 g. of sodium hydridein' ml. of 1,2-dimethoxyethane; 25 g. of methyl iodide are added; The reaction mixture is allowed to stand for several hours; then it is diluted with ethanol followed by water and extracted with methylene chloride. The extracts are combined, washed with water to neutrality, dried over sodium sulfate, filtered and evaporated to yield methyl 2-(6-methoxy-2-naphthyl)-propionate.

The resulting product is added to a mixture of 15 g. of sodium carbonate, 200 ml. of methanol and 25 ml. of water. The reaction mixture is allowed to stand for 24 hours; then the mixture is acidified with 200 ml. of two normal hydrochloric acid. The acidified mixture is combined, washed with water, dried over sodium sulfate and evaporated to yield 2-(6-methoxy-2-naphthyl)propionic-acid.

Similarly, the following 2-(6-substituted-2-naphthyl)- propionic acid derivatives are prepared from the corresponding 2-(6-substituted-2-naphthyl(acetic acid derivativesz- 2-(6-methyl-2-naphthyl)propionic acid, 2-'(6'-'ethyl-2'-naphthyl)propionic acid, 2-(6-isopropyl 2-naphthyl)propionic acid, 2-(6 cyclopropyl-2-naphthyl)propionic acid,

2-( trifluoromethyl-2-naphthyl)propionic acid,

*2.-"( 6ev inyl-2 naphthyl)propionic acid,

2(6 -ethynyl 2-naphthyl )propionic acid,

I 2-(6 fluoro 2-naphthyl,)propionic acid,

2-(6-chloro-Z naphthyDpropiOnic acid, 2- (6-methoxy 2-naphthyl)propionic acid,

2-(6-methoxymethyloxy-2-naphthyl)propionic acid, 2-(6-difluoromethoxy-Z-naphthyl)propionic acid, 2-(6-methylthio-2-naphthyl)pr0pianic acid, 2-(6-methoxymethylthio-2-naphthyl)propionic acid,

and 2-(6-difluoromethylthio-2-naphthyl)propionic acid.

PREPARATION 3 A 230 g. portion of dl 2-(6-methoxy-2-naphthyl)propionic acid in methanol is dissolved in 4.6.1. of warm methanol. The resulting solution is boiled until it becomes turbid; then sufficient methanol is added to make the solution clear again. This hot solution is added to a solution of 296 g. of cinchonidine in 7.4 l. of methanol heated to about 60C. The solutions are combined while stirring, and the combined mixture is then allowed to reach room temperature over a 2 hour period. After the reaction mixture has reached room temperature, it is stirred for an additional 2 hours and then filtered. The filtered solids are washed with several portions of cold methanol and dried.

100 Grams of the cinchonidine salt crystals are added to a stirred mixture of 600 ml. of ethyl acetate and 450 ml. of a 2 N aqueous hydrochloric acid. After the mixture has been stirred for 2 hours, the ethyl acetate layer is removed and washed with water to neutrality, dried over sodium sulfate and evaporated to yield d 2-(6- methoxy-2naphthyl)propionic acid.

PREPARATION 4 To a mixture of 0,4 g. of lithium aluminum hydride and 100 ml. of ethyl ether, there is added a mixture of 2.3 g. of d 2-(6-methoxy-2-naphthyl)propionic acid and 100 ml. of ethyl ether. The mixture is stirred at 0C for 30 minutes, and ml. of ethyl acetate is added. After 1 hour, 4 ml. of water is added to the mixture. The resulting mixture is filtered and evaporated under reduced pressure to yield 1 2-(6-methoxy-2-naphthyl)- I-propanol Repeating the above procedure with the d isomers of the compounds of Preparation 2 yields the corresponding optical isomers of 2-(6-substituted-2-naphthyl)-lpropanols.

This invention is further illustrated by the following specific but non-limiting examples.

EXAMPLE I A solution of 23 g. of d 2-(6-methoxy-2-naphthyl)- propionic acid in 100 ml. of benzene and ml. of thionyl chloride is heated under reflux for 2 hours. The reaction mixture is then evaporated in vacuo to yield the corresponding acid chloride. A solution of the residue in 300 ml. of tetrahydrofuran is cooled to -80C and treated with 47 g. of lithium aluminum tritertiarybutoxyhydride (2 molar equivalents). After stirring the reaction mixture at this temperature for 1 hour, the mixture is allowed to warm up to room temperature and is poured into water. The mixture is then extracted with benzene, and the organic phase is evaporated in vacuo to yield d 2-(6-methoxy-2-naphthyl)-propanal which is recrystallized from dichloromethane-hexane.

Repeating this procedure with the other d isomers of the compounds of Preparation 2 yields the corresponding d 2-(6-substituted-2-naphthyl)propanal derivatives, e.g. cl 2-(6-methyl-2-naphthyl)propanal, d 2-(6-ethyl- 2-naphthyl)propanal, d 2-(6-isopropyl-2- naphthyl)propanal, d 2-(6-cyclopropyl-2- naphthyl)propanal, d 2-(6-fluoro-2-naphthyl)propanal,

d 2-(6-chloro-2-naphthyl)propanal, d 2-(6- trifluoromethyl-2-naphthyl)propanal, d 2-(6- methylthio-2-naphthyl)propanal, d 2-(6-vinyl-2- naphthyl)propanal, d 2-(6-difluoromethoxy-2- naphthyl)propanal and d 2-(6-difluoromethylthio-2- naphthyl)-propanal.

EXAMPLE 2 A solution of 580 mg. of l 2-(6-methoxy-2- naphthyl)-l-propanol in 25 ml. of dichloromethane is treated with 2.9 g. of chromium trioxide-pyridine complex and stirred at room temperature for 5 hours. The mixture is then poured onto a column of silica gel. Elution with dichloromethane yields 260 mg. of d 2-(6- methoxy-2-naphthyl)propanal which is recrystallized from dichloromethane-hexane. (m.p. 72C, [a],,+l5 1 in dioxane).

Repeating the above procedure with the other products of Preparation 4 yields the corresponding d 2-(6- substituted-Z-naphthyl)propanals, e.g. d 2-(6-methyl- 2-naphthyl)propanal, d 2-(6-ethyl-2- naphthyl)propanal, d 2-(6-isopropyl-2-naphthyl)- propanal, d 2-(6-cyclopropyl-2-naphthyl)propanal, d 2-(6-fluoro-2-naphthyl)propanal, d 2-(6-chloro-2- naphthyl)propanal, d 2-(6-trifluoromethyl-2- naphthyl)propanal, d 2-(6-methylthio-2- naphthyl)propanal, d 2-(6-vinyl-2-naphthyl)-propanal, d 2-(6-difluoromethoxy-Z-naphthyl)propanal and d 2- (6-difluoromethylthio-2-naphthyl)propanal.

EXAMPLE 3 Ingredients Quantity per tablet,

mgs.

d 2-(6-methoxy-2-naphthyl)propanal l0 cornstarch 200 sucrose 40 The above ingredients are thoroughly mixed and pressed into single scored tablets.

EXAMPLE 4 Ingredients Quantity per tablet,

mgs.

d 2-(6-rnethoxy-2-naphthyl)propanal 2S cornstarch IOO lactose 393 magnesium stearate 2 The above ingredients are mixed intimately and The above ingredients are mixed and introduced into a hard-shell gelatin capsule.

We claim:

l. A d 2-(6-substituted-2-naphthyl)propanal selected from the group of compounds represented by the formula wherein R is methyl, ethyl, isopropyl, cyclopropyl, trifluoromethyl, vinyl, ethynyl, fluoro, chloro, methoxy, methoxymethyloxy, difluoromethoxy, methylthio, me- 

1. A D 2-(6-SUBSTITUTED-2-NAPHTHYL)PROPANAL SELECTED FROM THE GROUP OF COMPOUNDS REPRESENTED BY THE FORMULA
 2. As a compound of claim 1, d 2-(6-methylthio-2-naphthyl)propanal.
 3. As a compound of claim 1, d 2-(6-methyl-2-naphthyl)-propanal.
 4. As a compound of claim 1, d 2-(6-difluoromethoxy-2-naphthyl)propanal.
 5. As a compound of claim 1, d 2-(6-chloro-2-naphthyl)-propanal.
 6. As a compound of claim 1, pure, substantially isomer free, d 2-(6-methoxy-2-naphthyl)propanal, melting at about 70*-72*C. 